The present invention relates to a process for making compounds in the form of a stereoisomer or mixture thereof, of 16-phenoxy and 16-(o, m or p)-substituted phenoxy prostaglandin derivatives represented by the following formula ##STR2## wherein R is hydrogen, lower alkyl; X is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, and the wavy lines represent the .alpha. or .beta. configuration with the proviso that when one wavy line is .alpha. the other is .beta., or a pharmaceutically acceptable, non-toxic salt of the compound wherein R is hydrogen; certain novel intermediates for making these compounds and a stereoisomer of the compound of formula I wherein R is methyl and X is hydrogen and a process for preparing same.
The compounds of formula I are disclosed in U.S. Pat. No. 4,178,457.
The synthesis described herein addresses the twin problems of how to prepare an individual stereoisomer of the subject compounds while allowing selective deprotection of the C-9 hydroxyl group so it can be oxidized without also oxidizing the C-11 and C-15 groups and that the subsequent deprotection of C-11 and C-15 will not degrade the resulting molecule.
The problem of preparing an individual stereoisomer is solved by going through a novel propargyl alcohol intermediate which, though it is made as a diastereomeric mixture, can be separated into its two stereochemically pure isomers. One isomer of this stereochemically pure propargyl alcohol is then converted to a single, stereochemically pure allenic compound by employing a stereospecific homologation/rearrangement reaction in the next step. Starting with a specific stereochemically pure phenoxy lactone compound, which is available in the art, one can open the lactone and convert the resulting acid to an aldehyde. This novel aldehyde is reacted with a metal acetylide to give a propargyl alcohol having two stereoisomers. The two isomers can be separated into two stereochemically pure fractions by chromatographic means where one has properly selected one ether-forming protecting groups at C-9, C-11 and C-15, particularly at C-9. It has been found that a bulky ether-forming group at C-9 is necessary to effect readily this separation. For example, when the C-9 hydroxyl protecting group is an appropriate alkyl, aryl or arylalkyl substituted silyl ether, separation of the two propargyl alcohol isomers may be readily effected where otherwise separation is usually difficult and incomplete. The second essential step is to convert one stereochemically pure isomer to a single stereochemically pure allene-containing compound. This is accomplished by a hologation/rearrangement reaction using a trialkyl orthoacetate reagent and temperature.
The other problem is to design a synthetic sequence which will allow selective deprotection of the C-9 hydroxyl group so it can be oxidized, and then removal of the C-11 and C-15 hydroxyl protection groups without decomposing the resulting molecule. This is accomplished here by protecting C-9 with a base-labile ether-forming group while protecting C-11 and C-15 with base-stabile ether-forming groups. Then it is possible to drop off the C-9 protecting group, oxidize the hydroxyl group and then deprotect C-11 and C-15 under mild acid conditions. This sequence is essential because base would cause elimination-rearrangement to the "B" type prostaglandin and catalytic hydrogenation would affect the allene group.
The described process also provides an efficient method of preparing the compounds of U.S. Pat. No. 4,178,457, in particular in the form of mixtures of the four components which are included in formula I as defined below.
The compounds of U.S. Pat. No. 4,178,457 are known to be useful in the treatment of mammals where prostaglandins are indicated. They are particularly useful as inhibitors of gastric secretion. It has also been found that the stereoisomer of the compound of formula I possessing the R allene configuration wherein R is methyl and X is hydrogen having the following structure ##STR3## has excellent biological properties (for example potency, low toxicity etc.) and other properties which affect its pharmaceutical use (for example chemical stability, shelf life etc.). A study conducted in rats showed that the antisecretory ED.sub.50 for this individual R allenic stereoisomer is about 6 .mu.g/Kg.
Furthermore, this R allenic stereoisomer occurs in crystalline form.
Prostaglandins often are oily materials. The racemic diastereoisomeric mixture of the compounds of formula I wherein R is methyl and X is hydrogen is known to be a viscous oil (see U.S. Pat. No. 4,178,457) or low melting waxy solid. The compound which is structurally closest to the R allene stereoisomer of formula I' and its racemic diastereoisiomeric mixture, namely (dl) 9.alpha.,11.alpha.,15.alpha.-trihydroxy-16-phenoxy-17,18,19,20-tetranorpro sta-4,5,13(E)-trienoic acid methyl ester (a compound in Example 16 of U.S. Pat. No. 3,985,791) also occurs as an oil. The R allenic stereoisomer of formula I' was first obtained as an oil, but when stored in the freezer to be stabilized, surprisingly, the oily material spontaneously crystallized. The crystallized material has a melting point above 70.degree. C. In contrast with this isomer, the corresponding racemic diastereoisiomeric mixture, when stored in the freezer under the same conditions, takes about 1-3 weeks to become waxy solid. The S allene stereoisomer corresponding to formula I' never crystallized under similar conditions.
In addition, it was reported in UK Pat. No. 1,288,174, U.S. Pat. No. 4,005,133 and EPO Publication No. 97,439 that in order to have free-flowing crystalline solid materials, prostaglandins had to be converted into their organic or inorganic salts. Therefore, it is also surprising that the R allenic stereoisomer of formula I', without being converted into a salt, is a free-flowing crystalline material.
The crystalline material of formula I' can be easily purified using conventional techniques. The crystallinity of this material facilitates handling and chemical analysis and improves chemical stability. Furthermore, the crystalline material of formula I' can be readily formulated into solid dosage forms.